Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels

  • Bioorg Med Chem Lett. 2021 Jun 1;41:128025. doi: 10.1016/j.bmcl.2021.128025.
Hao Shao  1 ,  Xiaokai Li  2 ,  Shigenari Hayashi  3 ,  Jeanette L Bertron  2 ,  Daniel M C Schwarz  2 ,  Benjamin C Tang  3 ,  Jason E Gestwicki  4
Affiliations
  • 1. Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, United States; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, United States.
  • 3. Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, United States.
  • 4. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, United States; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, United States. Electronic address: [email protected].
PMID: 33839251 DOI: 10.1016/j.bmcl.2021.128025
Abstract

The molecular chaperone, Heat Shock Protein 70 (HSP70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric HSP70 Inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of HSP70 are expected to be useful tools for studying tau homeostasis.

Keywords
Hsc70; Hsp72; Metabolism; Molecular chaperone; Neurodegeneration; Protein folding; Tauopathy.
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